This invention relates to a carrier base material that is combined with a therapeutically active medicament and formed into a solid, shaped unit dosage form having a controlled and sustained incremental release of the medicament upon administration. The carrier base material of this invention comprises a mixture of a water-soluble hydroxypropylmethylcellulose and an alkali metal carboxylate, which carrier base desirably may be present in an amount less than 30 weight-% of the dosage form thereby permitting the administration of high dosage medicaments.
The administration of a medicament which requires a high dosage for effective therapy mandates a single, potentially toxic, dose or multiple doses. Alternatively, controlled and sustained release of a medicament from a solid unit dosage form provides for continuous dosage from a single administration. However, in order to accommodate a sufficient amount of a high dosage medicament in a solid unit dosage form, without significantly increasing the size of the latter, it is necessary to utilize a carrier base material which is effective, at low concentrations, in retarding the release of the medicament.
Hydroxypropylmethylcelluloses have been widely used as binders, matrices or carrier bases in sustained release solid dosage forms containing active medicaments, accompanied by lubricants and excipients, as needed. Commercially available hydroxypropylmethylcellulose is actually a series of compounds, each of which has a different chemical structure and composition, with a methoxyl content within the range of 16.5 to 30 weight-% and a hydroxypropoxyl content within the range of 4 to 32 weight-%, and each of which is available in various viscosity grades.
Commercial designations of the various hydroxypropylmethylcelluloses are based on the viscosities of 2% aqueous solutions at 20.degree. C. The viscosities range from 5 to 100,000 cps (mPa.sec) and represent number average molecular weights ranging from below 10,000 to over 150,000, as calculated from the data in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).
Christenson and Dale (U.S. Pat. No. 3,065,143) and Huber, Dale and Christenson (J. Pharm. Sci., 55, 974 (1966)) disclosed the preparation of a sustained release drug tablet wherein a high viscosity grade, i.e. high molecular weight, hydroxypropylmethylcellulose, was present as binder to the extent of at least one third of the weight of the tablet. The binders included a 4000 mPa.sec viscosity grade hydroxypropylmethylcellulose, now known as Methocel E4M, having a 28-30 weight-% methoxyl content, a 7.5-12 weight-% hydroxypropoxyl content and a number average molecular weight of 93,000, as well as 4000 and 15,000 mPa.sec viscosity grades hydroxypropylmethylcelluloses, now known as Methocel K4M and K15M, respectively, having a 19-24 weight-% methoxyl content, a 4-12 weight-% hydroxypropoxyl content and number average molecular weights of 89,000 and 124,000, respectively.
Christenson and his coworkers proposed that water was rapidly absorbed and formed a gel barrier on the surface of the tablet. Drug release was controlled by drug diffusion from and attrition of the gel barrier.
Christenson and Huber (U.S. Pat. No. 3,590,117) reported that neither low nor high viscosity grade hydroxypropylmethylcelluloses made acceptable longlasting troches.
Lapidus (Dissertation, Rutgers State University, 1967) and Lapidus and Lordi (J. Pharm. Sci., 55, 840 (1966); 57, 1292 (1968)) reported on the use of 25 and 15,000 mPa.sec viscosity grades hydroxypropylmethylcelluloses having a 19-24 weight-% methoxyl content and 4-12 weight-% hydroxypropoxyl content, i.e., Methocel K25 and K15M, respectively, in compressed pharmaceutical tablets.
Salomon, Doelker and Buri (Pharm. Acta Helv., 54 (3), 82 (1979)) disclosed the need for more than 30 weight-% of a 15,000 mPa.sec viscosity grade hydroxypropylmethylcellulose with 19-24 weight-% methoxyl content and 4-12 weight-% hydroxypropoxyl content (Methocel K15M) in a tablet containing potassium chloride, in order to sustain the release of drug for more than a few hours.
Sheth and Tossounian (U.S. Pat. Nos. 4,126,672; 4,140,755; 4,167,558) disclosed solid dosage forms containing 20-75% of a hydrocolloid such as 4000 mPa.sec viscosity grade hydroxypropylmethylcellulose in combination with various additives including gas-generating compounds, e.g. calcium carbonate, and inert fatty materials, resulting in a hydrodynamically balanced product having a bulk density of less than one when it is in contact with gastric fluid and hence floating on and releasing medicament therein.
Schor, Nigalaye and Gaylord (U.S. Pat. No. 4,389,393) disclosed sustained release solid unit dosage forms in which the carrier base material constituted less than one third of the weight of the dosage form and consisted of hydroxypropylmethylcellulose of at least 4000 mPa.sec viscosity grade, representing a number average molecular weight of at least 50,000, and having a methoxyl content of 16-24 weight-% and a hydroxypropoxyl content of 4-32 weight-%, e.g., Methocel J and Methocel K.
The use of high viscosity grades of hydroxypropylmethylcelluloses, Methocel E, F and K, in sustained release solid drug dosage forms is also described in a technical bulletin "Formulating Sustained Release Pharmaceutical Products with Methocel" (The Dow Chemical Co., 1982).
The prior art cited hereinabove discloses that high viscosity grades of hydroxypropylmethylcellulose of various chemical compositions are useful in the preparation of sustained release solid drug dosage forms. In contrast, Schor, Nigalaye and Gaylord (U.S. Pat. No. 4,369,172) disclosed that sustained release therapeutic compositions could be prepared by using as a carrier base material, a low viscosity grade hydroxypropylmethylcellulose having a hydroxypropoxyl content of 9-12 weight-% and a number average molecular weight of less than 50,000.
Lowey and Stafford (U.S. Pat. No. 3,870,790) and Schor (U.S. Pat. No. 4,226,849) disclosed that effective sustained release tablets were produced by using as carrier base material, a modified low viscosity grade hydroxypropylmethylcellulose having a hydroxypropoxyl content of less than 9 weight-% and a number average molecular weight of 23,000, e.g., Methocel E50. The modification was carried out by exposure of the low molecular weight hydroxypropylmethylcellulose to high humidity or moisture and drying in air, resulting in an increase in the carboxyl content of the polymer.
Davis and Gaylord (U.S. Pat. No. 4,540,566) and Daly, Davis and Kennerley (International J. Pharmaceutics, 18, 201 (1984)) disclosed that the presence of an alkali metal sulfate or sulfonate prolonged the release pattern of a medicament from a tablet containing the modified low viscosity grade hydroxypropylmethylcellulose as carrier base material.
Lowey (U.S. Pat. No. 4,259,314) disclosed the use of a mixture of dried hydroxypropylmethylcellulose having a viscosity in the range of 50 to 4000 mPa.sec, and hydroxypropylcellulose in the preparation of a controlled release pharmaceutical composition.
The present invention relates to further improvements in carrier base materials containing high molecular weight hydroxypropylmethylcelulose and high dosage prolonged release solid pharmaceutical unit dosage forms containing such improved carrier base materials. These improvements result from the presence of an alkali metal carboxylate in the carrier base material.